ketosis vs. ketoacidosis, part 2

Okay, I think I figured out yesterday's question about the etiology of ketoacidosis vs. ketosis. To recap, all the metabolic processes that lead to ketone production in ketoacidosis are present in ketosis, yet dietary carbohydrate starvation doesn't lead to an acidotic condition. This left me wondering what, exactly, causes ketoacidosis.

I feel pretty good about my conclusions yesterday. I narrowed down the cause to relative acidosis caused by volume depletion associated with the hyperglycemia that is not present in starvation, or an imbalance in the production-to-utilization ratio in ketosis. (If the body could burn and/or excrete ketones as fast as it produced them, there would be no acidosis.) And in fact, one of these was the reason.

First, as to the hyperglycemia-dehydration hypothesis, I discovered a condition called "euglycemic diabetic ketoacidosis," which pretty much rules that one out. Interestingly, while a western medical journal referred to this as a rare condition, a Pakistani medical journal says it accounts for 30% of patients presenting with DKA. I wonder what would account for that?

I finally found the answer in section 8.2 of Kerry Brandis' Acid-Base Physiology, an outstanding (and open access!) publication I had run across before but forgotten about. It's quite simple. Insulin is an antagonist to free fatty-acid release by cells. Without insulin, higher rates of free fatty-acids are available to act as increased substrate for ketone production. The odd imbalanced ratio of acetoacetate-to-ß-hydroxybutyrate is caused by an imbalance in NAD+to-NADH ratio caused by lactic acidosis.

I don't think I ever could have figured this out on my own because the answer depends on knowing rates. I would have had to figure out all the math behind the physiology first. So, I don't feel too bad.

Of course, that's not the whole story. FFA production is also increased by stress hormones, which explains why DKA is often precipitated by an infection.

Also, it appears that there may be some contribution of the feeding state on the rate of ketone uptake by mitochondria. I wonder about this one though. Essentially, it's suggested that in starvation ketone uptake is accelerated by glucagon, but as we know glucagon and other catabolic hormones rise in DKA. Again, it's a question of degree, I guess. Maybe glucagon is much higher in starvation.

Two articles that should have led me to the answer are the eMedicine articles on DKA and AKA. Actually, I did look at them yesterday. Not sure why they didn't register.

Finally, I almost went down a wrong path today looking at Dr. Johan Koeslag's article on oxalaoacetate. He suggests that glycogen is a necessity in order for cells to upregulate mitochondrial metabolism. Consider, then, a cell metabolism model focused on both fuel and rate regulation. The body might interpret the lack of normal fuel as a state of exertion rather than pathology and try to upregulate mitochondria, but, unable to do this in a state of glycogen depletion, then try to increase metabolic outputs by increasing substrates. I'm not totally convinced that there isn't something here. You will find some connection between DM1, DKA, and enlarged liver from over-storage of glycogen, for instance, if you start Googling.

Anyhow, I'm done with this for now. I think my Nur464 instructor should be encouraged for getting me to back and focus on the insulin issue and not squelching my interest in physiology, as was done in previous courses. Of course, I'm probably going to fail Nur464 since this won't be on the tests, but really that's all about the Community Health course, not this little side distraction...

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